Combinatorial chemistry has become a powerful tool for drug discovery in the pharmaceutical and biotechnology industries. Generally speaking, combinatorial chemistry is defined as the repetitive and systematic covalent attachment of different structural moieties to one another to produce a mixture of numerous distinct molecular entities or target molecules (i.e., combinatorial libraries). Desired target molecules include for example, peptides, oligonucleotides, and small organic molecules. Frequently, combinatorial chemistry is utilized to generate a group of structurally related analogs, which can then be evaluated to establish structure-activity relationships (SAR) and to optimize biological efficacy.
The prominence of the indole nucleus in medicinally important natural products and synthetic pharmaceuticals can hardly be overstated. (see, Gribble, in Comprehensive Heterocyclic Chemistry II, 2:207 (1996); Ban, et al., N. Med. Res. Rev., 8(2):231 (1998); Saxton, The Chemistry of Heterocyclic Compounds; Wiley; New York, Vol. 25, Part IV (1983).) As a result, the chemistry of the substituted indole has received an enormous amount of attention. (see, Gribble, G. W. J. Chem. Soc. Perkin Trans. 1, 1045 (2000); Sundberg, in Comprehensive Heterocyclic Chemistry II, 2:119 (1996); Hughes, Org. Prep. Proc. Int., 607 (1993)) The revolution of combinatorial chemistry of small molecules (see, Gordon, et al., J. Med. Chem., 37(10):1385 (1994); Thompson, et al., Chem. Rev., 96:555 (1996); Balkenhohl, et al., Angew. Chem. Int. Ed. Enlg., 35:2288 (1996)) assured that the synthesis of indole containing lead compounds would be accelerated in a similar manner to all other scaffolds. (see, Hutchins, et al., Tetrahedron Lett., 37(28):4869 (1996); Yun, et al., Tetrahedron Lett., 37(40):7189 (1996); Hughes, Tetrahedron Lett., 37(42):7595 (1996); Cheng, et al., Tetrahedron Lett., 38(9):1497 (1997); Fagnola, et al., Tetrahedron Lett., 38(13):2307 (1997); Zhang, et al., J. Org. Chem., 62:1804 (1997); Arumugam, et al., Tetrahedron Lett., 38(36):6473 (1997); Collini, et al., Tetrahedron Lett., 38(46):7963 (1997); Fokas, et al., Tetrahedron Lett., 39:2235 (1998); Zhang, et al., Tetrahedron Lett., 39:4449 (1998); Smith, et al., Tetrahedron Lett., 39:8317 (1998); Wang, Y. et al., Tetrahedron Lett., 39:9605 (1998); Stephensen, et al., Tetrahedron Lett., 40:5799 (1999); Wang, et al., Org. Lett., 1(10):1647 (1999); Zhang, et al., Org. Lett., 2(1):89 (2000); Kraxner, et al., Synlett, (1): 125 (2000); Tois, et al., Tetrahedron Lett., 41:2443 (2000); Ketcha, et al., Tetrahedron Lett., 41:6253 (2000); Smith, et al., Bioorg. Med. Chem. Lett., 10:2693 (2000); Stevenson, et al., Bioorg. Med. Chem. Lett., 10:2697 (2000); Nettekoven, Tetrahedron Lett., 41:8251 (2000); Meseguer, et al., Chem. Eur. J., 6(21):3943 (2001); Cooper, et al., Bioorg. Med. Chem. Lett., 11:1233 (2001).)
Biologically important indoles have a variety of activities and are useful for a number of indications. For example, lysergic acid diethyl amide has an indole core and is a hallucinogen and CNS activator (see, Jenner, et al., Br. J. Pharmocol., 80, Suppl. 667P (1983); Kaiser, et al., Med. Res. Rev., 5:145 (1985)). This indole also has a plethora of physiological effects (see, Bowers, et al., Biochem. Pharmocol., 31:4093 (1982); Mornex, et al., J. Pharmocol., 14 (Suppl. 3), 81 (1983)). Hippadine, another indole containing core molecule, causes reversible inhibition of fertility in male rats without anti-mitotic activity (see, Bowers, et al., Biochem. Pharmocol., 31:4093 (1982); Mornex, et al., J. Pharmocol., 14 (Suppl. 3), 81 (1983)). Moreover, (−)-7-octylindolactam V is a protein kinase C modulator and it too has an indole core (see, Kazanietz et al., Mol. Pharmacol., 44:298 (1993)). The structural properties that these molecules share is their substitution at the 4 and 7 positions of the indole nucleus.
The tremendous variety of biological activities associated with indoles makes the indole nucleus very important biologically. What is needed in the art are new indoles having a variety of substituents at the 4 and 7 positions of the indole ring. The present invention satisfies this and other needs.